Certain aminomethyl biphenyl, aminomethyl phenyl pyridine and aminomethyl phenyl pyrimidine derivatives; novel dopamine receptor subtype selective ligands

ABSTRACT

Disclosed are compounds of the formula:                    
     where 
     S and V are various organic or inorganic substituents; 
     G and K are the same or different and represent N or CR′ where R′ is an organic or inorganic substituent; 
     R is hydrogen or an alkyl group; 
     R 1 , X, Y, Z and T are organic or inorganic substituents; and 
     R 2  and R 3  represent hydrogen or organic substituents; or 
     NR 2 R 3  together represents a heterocyclic ring system; 
     and the pharmaceutically acceptable salts thereof; which are highly selective partial agonists or antagonists at brain dopamine receptor subtypes and, thus, are useful in the diagnosis and treatment of affective disorders such as schizophrenia and depression as well as certain movement disorders such as Parkinsonism.

This a continuation of application Ser. No. 08/946,841, filed Oct. 8,1997 now U.S. Pat. No. 5,912,350; which is a continuation of Ser. No.08/457,633, filed Jun. 1, 1995 now U.S. Pat. No. 5,677,454; which is acontinuation of Ser. No. 08/344,497 filed Nov. 23, 1994, now U.S. Pat.No. 5,594,141.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to certain aminomethyl biphenyl, phenylpyridinesand phenylpyrimidine derivatives which selectively bind to braindopamine receptor subtypes. This invention also relates topharmaceutical compositions comprising such compounds. It furtherrelates to the use of such compounds in treating affective disorderssuch as schizophrenia and depression as well as certain movementdisorders such as Parkinsonism.

2. Description of the Related Art

Schizophrenia or psychosis is a term used to describe a group ofillnesses of unknown origin which affect approximately 2.5 millionpeople in the United States. These disorders of the brain arecharacterized by a variety of symptoms which are classified as positivesymptoms (disordered thought, hallucinations and delusions) and negativesymptoms (social withdrawal and unresponsiveness). These disorders havean age of onset in adolescence or early adulthood and persist for manyyears. The disorders tend to become more severe during the patient'slifetime and can result in prolonged institutionalization. In the UnitedStates today, approximately 40% of all hospitalized psychiatric patientssuffer from schizophrenia.

During the 1950's physicians demonstrated that they could successfullytreat psychotic patients with medications called neuroleptics; thisclassification of antipsychotic medication was based largely on theactivating (neuroleptic) properties of the nervous system by thesedrugs. Subsequently, neuroleptic agents were shown to increase theconcentrations of dopamine metabolites in the brain suggesting alteredneuronal firing of the doparnine system. Additional evidence indicatedthat doparnine could increase the activity of adenylate cyclase in thecorpus striatum, an effect reversed by neuroleptic agents. Thus,cumulative evidence from these and later experiments strongly suggestedthat the neurotransmitter dopamine was involved in schizophrenia

One of the major actions of antipsychotic medication is the blockade ofdopamine receptors in brain. Several dopamine systems appear to exist inthe brain and at least five classes of dopamine receptors appear tomediate the actions of this transmitter. These dopamine receptors differin their pharmacological specificity and were originally classified uponthese differences in the pharmacology of different chemical series. Thebutyrophenones, a class of compounds containing many potentantipsychotic drugs, were quite weak at the dopamine receptor thatactivated adenylate cyclase (now known as a D1 dopamine receptor). Incontrast, they labelled other dopamine receptors (called D2 receptors)in the subnanomolar range and a third type, D3, in the nanomolar range.Two additional receptor subtypes have also been identified. D5, which issomewhat similar to the D1 receptor subtype, and D4 which is closelyrelated to D3 and D2 receptor types. The phenothiazines, which includechlorpromazine, possess nanomolar affinity for all three types ofdoparnine receptors. Other drugs have been developed with greatspecificity for the D1 receptor subtype and for the D2 receptor subtype.

A group of drugs (such as sulpiride and clozapine) have been developedwhich display a lesser incidence of extrapyramidal side effects thanclassical neuroleptics. In addition, there is some indication that thesedrugs may be more beneficial in treating negative symptoms in somepatients. Since all D2 blockers do not possess a similar profile,certain hypotheses underlying the differences have been investigated.One of the major differences among these various classes ofantipsychotics has been in the anticholinergic actions of these drugs.The possibility also exists that the various dopamine receptor subtypesmay be differentially distributed between the limbic areas, thought tomediate antipsychotic responses, and the motor areas of the brain. Theexistence of the D3, D4 and D5 and other as yet undiscovered dopaminereceptors may contribute to this profile. Atypical antipsychotics haveloosely been defined as those compounds which impart antipsychoticaction without the concurrent motor impairment. Some of the atypicalcompounds possess similar activity at both D2, D3 and D4 receptors. Theexamples of this patent fall into this general class of molecules.

Using molecular biological techniques it has been possible to clonecDNAs coding for each of the pharmacologically defined dopaminereceptors. There are at least two forms of D1-type receptors, which havebeen referred to as D1 and D5, and two forms of D2-type receptors,referred to now as D2 and D4 dopamine receptors. In addition, there isat least one form of D3 dopamine receptor. Examples from the aminomethylbiphenyl, aminomethyl phenylpyridines and aminomethyl phenylpyrimidinesseries of this patent possess differential affinities for each receptorsubtype.

SUMMARY OF THE INVENTION

This invention provides novel compounds of Formula I which interact withdopamine receptor subtypes.

The invention provides pharmaceutical compositions comprising compoundsof Formula I. The invention also provides compounds useful in treatingaffective disorders such as schizophrenia and depression as well ascertain movement disorders such as Parkinsonism. Furthermore compoundsof this invention may be useful in treating the extrapyramidyl sideeffects associated with the use of conventional neuroleptic agents.Since dopamine D3 and D4 receptor subtypes are concentrated in thelimbic system (Taubes, Science (1994) 265 1034) which controls cognitionand emotion, compounds which interact with these receptors may haveutility in the treatment of cognitive disorders. Such disorders may bethe cognitive deficits which are a significant component of the negativesymptoms (social withdrawal, and unresponsiveness) of schizophrenia.Other disorders involving memory impairment or attention deficitdisorders may also be treated with the compounds of this invention thatinteract specifically with dopamine D3 and/or D4 receptor subtypes.Accordingly, a broad embodiment of the invention is directed to acompound of Formula I:

where

S and V are the same or different and represent hydrogen, halogen,hydroxy, phenyl, straight or branched chain lower alkyl having 1-6carbon atoms, or straight or branched chain lower alkoxy having 1-6carbon atoms;

G and K are the same or different and represent N or CR′ where R′ ishydrogen, halogen, straight or branched chain lower alkyl having 1-6carbon atoms or straight or branched lower alkoxy having 1-6 carbonatoms;

R is hydrogen or straight or branched chain lower alkyl having 1-6carbon atoms;

R₁, X, Y, Z and T are the same or different and represent hydrogen,halogen, cyano, hydroxy, straight or branched chain lower alkyl having1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6carbon atoms or SO₂R₄ where R₄ is straight or branched chain lower alkylhaving 1-6 carbon atoms or where R₄ is NH₂ or NHCH₃;

R₂ and R₃ are the same or different and represent hydrogen, straight orbranched chain lower alkyl having 1-6 carbon atoms, aryl, arylalkyl; or

NR₂R₃ together represent 2-(1,2,3,4tetrahydroisoquinolinyl), eitherunsubstituted or mono or disubstituted with halogen, hydroxy, straightor branched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms; or NR₂R₃represents:

where R₅ is phenyl, either unsubstituted or mono or disubstituted byeither halogen, hydroxy, straight or branched chain lower alkyl having1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6carbon atoms; or

NR₂R₃ represents

where W is N or CH; and

R₆ is phenyl, benzyl, pyridyl or pyrimidinyl, unsubstituted or mono ordisubstituted with halogen, hydroxy, straight or branched chain loweralkyl having 1-6 carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms; and n is 1, 2 or 3.

The interaction of the aminomethyl biphenyl, aminomethyl phenylpyridinesand aminomethyl phenylpyrimidine derivatives of the invention withdopamine receptor subtypes results in the pharmacological activities ofthese compounds. These compounds are highly selective partial agonistsor antagonists at brain dopamine receptor subtypes or prodrugs thereofand are useful in the diagnosis and treatment of affective disorderssuch as schizophrenia and depression as well as certain movementdisorders such as Parkinsonism. Furthermore, compounds of this inventionare useful in treating the extrapyramidyl side effects associated withthe use of conventional neuroleptic agents.

Thus, the invention encompasses methods for the treatment ofneuropsychological disorders comprising administering to a patienthaving a neuropsychological disorder an amount of a compound accordingto Formula I effective to treat the neuropsychological disorder.

BRIEF DESCRIPTION OF THE DRAWING

FIGS. 1A-1L show representative aminomethyl biphenyls, aminomethylphenylpyridines and aminomethyl phenylpyrimidines of the presentinvention.

DETAILED DESCRIPTION OF THE INVENTION

In addition to compounds of general formula I described above, thepresent invention further encompasses compounds of Formula II:

where R₁, X, Y, Z and T represent hydrogen or alkyl; R₇ and R₈independently represent hydrogen or alkoxy; R₉ is hydrogen or alkyl; andW represents nitrogen or CH.

Preferred compounds of Formula I include those where W is N or CH; andR₇ is phenyl, pyridyl or pyrimidinyl, each of which is optionally monoor disubstituted with halogen, hydroxy, straight or branched chain loweralkyl having 1-6 carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms.

Preferred compounds according to Formula II are those where R₁, X, Y, Zand T are hydrogen; R₇ and R₈ are different and represent hydrogen oralkoxy; W is CH; and Ar represents benzyl or phenyl. Other preferredcompounds of Formula II are those where R₁, X, Y, Z and T are hydrogen;R₇ and R₈ are different and represent hydrogen or alkoxy; W is nitrogen;and Ar represents 2-pyridyl or pyrimidinyl.

The invention further encompasses compounds of Formula III:

where R₁, X, Y, Z and T represent hydrogen or alkyl and R₉ representshydrogen or alkyl.

Preferred compounds according to Formula III are those where R₁, X, Y, Zand T are hydrogen; R₉ represents hydrogen; and Ar represents benzyl orphenyl. Other preferred compounds of Formula III are those where R₁, X,Y, Z and T are hydrogen; R₉ represents hydrogen; and Ar represents2-pyridyl or pyrimidinyl.

The invention further encompasees compounds of Formula IV:

where R₁, X, Y, Z and T represent hydrogen or alkyl; and R₁₀ and R₁₁independently represent hydrogen or alkyl.

Preferred compoinds according to Formula IV are those where R₁, X, Y, Zand T are hydrogen; Ar represents phenyl; and R₁₀ and R₁₁ independentlyrepresent alkyl. Other preferred compounds of Formula IV are those whereR₁, X, Y, Z and T are hydrogen; R₁₀ and R₁₁ independently representmethyl; and Ar represents phenyl.

The invention further encompasses compounds of Formula V:

where R₁, X, Y, Z and T represent hydrogen or alkyl; R₉ is hydrogen oralkyl; R₁₀ represents hydrogen or akyl; and R₁₂ represents alkoxy.

Preferred compounds according to Fornula V are those where R₁, X, Y, Zand T are hydrogen; R₉ is hydrogen; R₁₀ represents alkyl and R₁₂ is analkoxy group in the 2-position of the phenyl ring.

The invention further encompasses compounds of Formula VI:

where R₁, X, Y, Z and T represent hydrogen or alkyl; and R_(C) is agroup of the formula:

where

W is N or CH;

R represents alky; and

R_(d) represents pyridyl, pyrimidinyl, phenylalkyl, or phenyl optionallysubstituted with halogen, alkyl or alkoxy.

Preferred compounds according to Formula VI are those where R₁, X, Y, Zand T are hydrogen; Ar is optionally substituted phenyl and R_(c) is a4substituted piperazin-1-yl or piperidin-1-yl group. Particularlypreferred compounds of Formula VI are those where the 4-substitutedpiperazin-1-yl or piperidin-1-yl groups are substituted with optionallysubstituted phenyl, phenylalkyl, 2-pyridyl or 2-pyrimidinyl groups.

The invention further provides compounds of Formula VII.

where R₁, X, Y, Z and T represent hydrogen or alkyl; and R_(C) is agroup of the formula:

where

W is N or CH;

R represents alkyl; and

R_(d) represents pyridyl, pyrimidinyl, phenylalkyl, or phenyl optionallysubstituted with halogen, alkyl or alkoxy.

Preferred compounds according to Formula VII are those where R₁, X, Y, Zand T are hydrogen; and R_(c) is a 4-substituted piperazin-1-yl orpiperidin-1-yl group. Particularly preferred compounds of Formula VIIare those where the 4substituted piperazin-1-yl or piperidin-1-yl groupsare substituted with optionally substituted phenyl, phenylalkyl,2-pyridyl or 2-pyrimidinyl groups.

The invention further provides compounds of Formula VIII:

where R₁, X, Y, Z and T represent hydrogen or alkyl; and R_(c) is agroup of the formula:

where

W is N or CH;

R represents alkyl; and

R_(d) represents pyridyl, pyrimidinyl, phenylalkyl, or phenyl optionallysubstituted with halogen, alkyl or alkoxy.

Preferred compounds according to Formula VIII are those where R₁, X, Y,Z and T are hydrogen; and R_(c) is a 4-substituted piperazin-1-yl orpiperidin-1-yl group. Particularly preferred compounds of Formula VIIIare those where the 4substituted piperazin-1-yl or piperidin-1-yl groupsare substituted with optionally substituted phenyl, phenylalkyl,2-pyridyl or 2-pyrimidinyl groups.

The invention further provides compounds of Formula IX:

where R₁, X, Y, Z and T represent hydrogen or alkyl; and R_(c) is agroup of the formula:

where

W is N or CH;

R represents alkyl; and

R_(d) represents pyridyl, pyrimidinyl, phenylalkyl, or phenyl optionallysubstituted with halogen, alkyl or alkoxy.

Preferred compounds according to Formula IX are those where R₁, X, Y, Zand T are hydrogen; and R_(c) is a 4-substituted piperazin-1-yl orpiperidin-1-yl group. Particularly preferred compounds of Formula IX arethose where the 4-substituted piperazin-1-yl or piperidin-1-yl groupsare substituted with optionally substituted phenyl, phenylalkyl,2-pyridyl or 2-pyrimidinyl groups. Still other preferred compounds ofFormula IX are those where R_(c) is N-benzyl-N-methylamino.

Representative compounds of the present invention, which are encompassedby Formula I, include, but are not limited to the compounds in FIG. Iand their pharmaceutically acceptable salts. Non-toxic pharmaceuticallyacceptable salts include salts of acids such as hydrochloric,phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluene sulfonic,hydroiodic, acetic and the like. Those skilled in the art will recognizea wide variety of non-toxic pharmaceutically acceptable addition salts.

The present invention also encompasses the acylated prodrugs of thecompounds of Formula I. Those skilled in the art will recognize varioussynthetic methodologies which may be employed to prepare non-toxicpharmaceutically acceptable addition salts and acylated prodrugs of thecompounds encompassed by Formula I.

By aryl or “Ar” is meant an aromatic carbocyclic group having a singlering (e.g., phenyl), multiple rings (e.g., biphenyl), or multiplecondensed rings in which at least one is aromatic, (e.g.,1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl), whichcan optionally be unsubstituted or substituted with e.g., halogen, loweralkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy,aryl, heteroaryl, and hydroxy.

By alkyl and lower alkyl is meant straight and branched chain alkylgroups having from 1-6 carbon atoms.

By lower alkoxy and alkoxy is meant straight and branched chain alkoxygroups having from 1-6 carbon atoms.

By heteroaryl is meant 5, 6, or 7 membered aromatic ring systems havingat least one hetero atom selected from the group consisting of nitrogen,oxygen and sulfur. Examples of heteroaryl groups are pyridyl,pyrimidinyl, pyrrolyl, pyrazolyl, pyrazinyl, pyridazinyl, oxazolyl,furanyl, quinolinyl, isoquinolinyl, thiazolyl, and thienyl, which canoptionally be unsubstituted or substituted with e.g., halogen, loweralkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy,aryl, heteroaryl, and hydroxy.

By halogen is meant fluorine, chlorine, bromine and iodine.

By arylalkyl and aralkyl is meant the group —R—Ar where Ar is an arylgroup and R is a straight or branched chain aliphatic group. Arylalkylgroups may optionally be substituted with, e.g., halogen, lower alkyl,lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy, andhydroxy. Preferred arylalkyl groups in the above formulas where W is CHand R₈ represents arylalkyl are phenylalkyl groups where the alkylportion is lower alkyl. A particularly preferred phenylalkyl group isbenzyl where the phenyl ring may be substituted with up to threesubstituents independently selected from hydrogen, halogen,trifluoromethyl, hydroxy, straight or branched chain lower alkyl having1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6carbon atoms.

By cycloalkyl is meant cyclic hydrocarbons having from 3-8 carbon atoms.These cyclic hydrocarbon groups may be substituted with up to threesubstituents independendy selected from hydrogen, halogen,trifluoromethyl, cyano, straight or branched chain lower alkyl having1-6 carbon atoms, hydroxy, straight or branched chain lower alkyl having1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6carbon atoms, or SO₂R₉ where R₉ is NH₂ or NHCH₃.

The pharmaceutical utility of compounds of this invention are indicatedby the following assays for dopamine receptor subtype affinity.

Assay for D2 and D3 receptor binding activity

Striatial tissue is dissected from adult male Sprague Dawley rats or BHK293 cells are harvested containing recombinantly produced D2 or D3receptors. The sample is homogenized in 100 volumes (w/vol) of 0.05 MTris HCl buffer at 4° C. and pH 7.4. The sample is then centrifuged at30,000× g and resuspended and rehomogenized. The sample is thencentrifuged as described and the final tissue sample is frozen untiluse. The tissue is resuspended 1:20 (wt/vol) in 0.05 M Tris HCl buffercontaining 100 mM NaCl.

Incubations are carried out at 48° C. and contain 0.5 ml of tissuesample, 0.5 nM ³H-raclopride and the compound of interest in a totalincubation of 1.0 ml. Nonspecific binding is defined as that bindingfound in the presence of 10⁻⁴ M dopamine; without further additions,nonspecific binding is less than 20% of total binding. The bindingcharacteristics of examples of this patent are shown in Table 1 for ratstriatal homogenates.

TABLE I D2 binding D3 binding Compound Number¹ IC₅₀(μM) IC₅₀(μM) 1 0.1750.329 3 0.012 0.012 4 0.005 0.061 5 ND 2.490 6 ND 6.120 7 ND 0.342 81.940 ND 9 0.290 ND 10 ND 1.140 11 ND 1.612 ¹Compound numbers relate tocompounds shown in FIG. I. ND = Not Done

¹Compound numbers relate to compounds shown in FIG. I. ND=Not Done.

Assay for D4 receptor binding activity

Clonal cell lines expressing the human dopamine D4 receptor subtype wereharvested in PBS and the cells centrifuged and the pellets stored at−80° C. until used in the binding assay. The pellets were resuspendedand the cells lysed at 4° C. in 50 mM Tris pH 7.4 buffer containing 120mM NaCl, 1 mM EDTA and 5 mM MgCl₂. The homogenate is centrifuged at48000× g for 10 minutes at 4° C. The resulting pellet is resuspended infresh buffer and centrifuged again. After resuspension of the pellet infresh buffer a 100 ml aliquot is removed for protein determination. Theremaining homogenate is centrifuged as above, the supernatant removedand the pellet stored at 4° C. until needed; at which time it isresuspended to a final concentration of 625 mg/nm (250 mg per sample)with 50 mM Tris buffer (pH 7.4) and 120 mM NaCl just prior to use.Incubations were carried out for 60 minutes at 25° C. in the presence of0.1 nM [³H] YM-09151-2. The incubation was terminated by rapidfiltration through Whatman GF/C filters and rinsed with 2×4 ml washes ofchiled 50 mM Tris (pH 7.4) and 120 mM NaCl. Non-specific binding wasdetermined with 1 mM spiperone and radioactivity determined by countingin an LKB beta counter. Binding parameters were determined by non-linearleast squares regression analysis, from which the inhibition constant Kicould be calculated for each test compound. The binding characteristicsof some examples of this patent are shown in Table 2 for the dopamine D4binding assay. In general, compounds of the accompanying examples weretested in the above assay, and all were found to possess a Ki value forthe displacement of [³H]YM-09151-2 from the human dopamine D4 receptorsubtype of below 500 nM. Some specific data is indicated in Table 2.

TABLE 2 Compound Number¹ Ki(μM) 1 0.032 2 0.243 3 0.018 4 0.028 5 0.2866 >0.075 7 >0.075 8 1.055 9 0.056 10 0.769 11 0.600

Compounds 1, 3, 4 and 9 are particularly preferred embodiments of thepresent invention because of their potency in binding to doparninereceptor subtypes.

The compounds of the invention including those represented by generalFormula I may be administered orally, topically, parenterally, byinhalation or spray or rectally in dosage unit formulations containingconventional non-toxic pharmaceutically acceptable carriers, adjuvantsand vehicles. The term parenteral as used herein includes subcutaneousinjections, intravenous, intramuscular, intrasternal injection orinfusion techniques. In addition, there is provided a pharmaceuticalformulation comprising a compound of general Formula I and apharmaceutically acceptable carrier. One or more compounds of generalFormula I may be present in association with one or more non-toxicpharmaceutically acceptable carriers and/or diluents and/or adjuvantsand if desired other active ingredients. The pharmaceutical compositionscontaining compounds of general formula I may be in a form suitable fororal use, for example, as tablets, troches, lozenges, aqueous or oilysuspensions, dispersible powders or granules, emulsion, hard or softcapsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oiL liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occuiring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitor or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be sterile injectablesolution or suspension in a non-toxic parentally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of general formula I may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Compounds of general formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anaesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

An illustration of the preparation of representative aminomethylbiphenyls, aminomethyl phenyl pyridines and aminomethyl phenylpyrimidines of the present invention is given in Scheme I. Those havingskill in the art will recognize that the starting materials may bevaried and additional steps employed to produce compounds encompassed bythe present invention. The substituents R′, R₁, R₂, R₃, S, T, V, X, Y,and Z carry the definitions set forth above for Formula I.

This invention is further illustrated by the following examples whichare not to be construed as limiting the invention in scope or spirit tothe specific procedures and compounds described therein.

Example I

A mixture of 1.1 g of 2-(chloromethyl)-4-bromoanisole, 1 g of1-(2-pyrimidyl)piperazine dihydrochloride and 2.0 mLN,N-diisopropylethylamine in 10 mL chloroform was heated at refluxtemperature for 2 hr, cooled to room temperature, washed with 1 N NaOHand water. The solvent was removed by evaporation under reduced pressureto yield 3.6 g of2-[(4-(2-pyrimidinyl)-piperazinyl)methyl]-4-bromoanisole as a whitesolid which was used in the next step without further purification.

A solution of 182 mg 2-[(4(2-pyrimidinyl)-piperazinyl)methyl]-4-bromoanisole in 1 mL of tetrahydrofuran heated to 60° C. and 6 mg ofPd(PPh₃)₄ was added. To this mixture 0.5 mL of a 1 M solution ofphenylmagnesium bromide in tetrahydrofulran was added dropwise. Thereaction mixture was heated at relux temperature under nitrogen for 1hr, cooled to room temperature and the solvent removed by evaporationunder reduced pressure to yield4-phenyl-2-[(4-(2-pyrimidinyl)-piperazinyl)methyl]anisole which waspurified by chromatography on silica gel using 5% methanol indichloromethane as eluent. Evaporation of the solvent yielded 140 mg ofa solid which was treated with ethyl acetate-HCl to give 50 mg of4phenyl-2-[(4-(2-pyrimidinyl)-piperazinyl)methyl]-anisoledihydrochloride (Compound 1), mp 205-207° C.

Example II

A mixture of 1.1 g of 4(chloromethyl)-2-bromoanisole 1.0 g1-(2-pyrimidyl)piperazine dihydrochloride and 2.0 mL ofN,N-diisopropylethylamine in 10 mL chloroform was heated at refluxtemperature for 2 hr, cooled to room temperature, washed with 1 N NaOHand water. The solvent was removed by evaporation under reduced pressureto give 3.4 g of4-[(4-(2-pyrimidinyl)-piperazinyl)methyl]-2-bromoanisole as a whitesolid which was used in the next step without further purification orcharacterization.

To a solution of 181 mg4-[(4-(2-pyrimidinyl)-piperazinyl)methyl]-2-bromoanisole in 2 mL ofdimethylformamide was added phenylboric acid (91.5 mg), triethylamine(152 mg), palladium acetate (3.4 mg) and triphenylphosphine (8.1 mg).The reaction mixture was heated at 100° C. under nitrogen for 4 hr,cooled to room temperature and partitioned between dilute ammoniumhydroxide and dichloromethane. The organic layer was washed with waterand the solvent removed by evaporation under reduced pressure to2-phenyl-4-[(4-(2-pyrimidinyl)-piperazinyl)methyl]anisole which waspurified by reverse phase chromatography on C18 resin using amethanol-water mixture (4:1) as eluenL

Evaporation of the solvent yielded 10 mg of a solid which was treatedwith ethereal-HCl to give 10 mg of2-phenyl-4-[(4-(2-pyrimidinyl)-piperazinyl)methyl]anisoledihydrochloride (Compound 2), mp 213-215° C.

Example III

To a suspension of 100 mg of lithium aluminum hydride in 20 mL of etherwas added 500 mg 3-phenylbenzoic acid. The reaction mixture was stirredat room temperature overnight. After any excess lithium aluminum hydridewas destroyed with water, the organic layer was washed successively with25 mL aliquots of dilute hydrochloric acid, dilute sodium hydroxide andbrine. The organic phase was dried over anhydrous sodium sulfate and thesolvent removed by evaporation under reduced pressure to yield 360 mg of3-hydroxymethylbiphenyl as a crystalline solid. This material was usedin the next step without further purification.

A solution of 50 mg of 3-hydroxymethylbiphenyl in 1.5 mL thionylchloride was heated at reflux temperature for 4 hr, cooled to roomtemperature and the solvent removed by evaporation under reducedpressure to yield 45 mg of 3-chloromethylbiphenyl which was used in thenext step without further purification or characterization.

To a solution of 45 mg of 3-chloromethylbiphenyl in 5 mL of chloroformwas added 50 mg of 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride and0.5 mL triethylamine. The reaction mixture was heated at refluxtemperature overnight, cooled to room temperature, washed successivelywith 50 mL aliquots of dilute sodim hydroxide and brine. The chloroformwas removed by evaporation under reduced pressure to yield3-phenyl[(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)methyl]benzene whichwas purified by chromatography on silica gel using 5% methanol indichloromethane as eluent. Evaporation of the solvent yielded a solidwhich was treated with ethereal-HCl to give 15 mg of3-[(4-1,2,3,6-tetrahydropyridin-1-yl)methyl]biphenyl hydrochloride(Compound 3), mp 236-238° C.

Example IV

The following compounds were prepared essentially according to theprocedure described in Example III.

(a) 3-[(4phenyl-piperidin-1-yl)methyl]biphenyl hydrochloride (Compound4).

(b) 3-phenyl-6-[(4-benzyl-piperidin-1-yl)methyl]toluenehydrochloride(Compound 5), mp 215-217° C.

(c) 3-[(N-methyl-N-benzyl)aminomethyl]biphenyl hydrochloride, mp184-187° C.

(d) N-(1-(3-biphenyl)ethyl-N-methylbenzylamine hydrochloride (Compound6), mp 143-145° C.

(e) 1-(2-methoxyphenyl)-4-(1-(3-biphenyl)ethyl)piperazinedihydrochloride (Compound 7), mp 181-183° C.

(f) 1-(2-pyrimidyl)-4-((3, 5-diphenylphenyl)methyl)piperazinedihydrochloride (Compound 8), mp 212-214° C.

Example V

To a solution of 5.0 g of 2-hydroxy-4methylpyridine in 70 mL of pyridineat 0° C. was added 13.3 g triflic anhydride dropwise. The reaction wasstirred at 0° C. for 15 minutes and then allowed to warm to roomtemperature. After removal of the volatile reactants under reducedpressure, the residue was partitioned between 100 mL of ethyl acetateand 100 mL of 10% sodium carbonate solution. The organic layer waswashed with 100 mL of brine and the solvent removed by evaporation underreduced pressure. The resulting oil was vacuum distilled at 150° C. (25mm Hg) to provide 10.5 g of 2-trifluoromethanesulfonyl-4-methylpyridineas a colorless oil.

To a solution of 1.65 g 2-trifluoromethanesulfonyl-4-methylpyridine in30 mL of dimethylformamide and 30 mL of dioxane was added PdCl₂(PPh₃)₂(400 mg), lithium chloride (873 mg) and tetraphenyltin (10.5 g). Thereaction mixture was heated at reflux temperature for 3 hr, cooled toroom temperature and filtered. The filtrate was diluted with 1 Nhydrochloric acid, washed with 250 mL ether, then basified with 2 Nsodium hydroxide and extracted with 2×250 mL of ethyl acetate. Thecombined extracts were washed with 150 mL water, separated and the ethylacetate removed by evaporation under reduced pressure to yield 900 mg of2-phenyl-4-methylpyridine as an oil.

To a solution of 100 mg of 2-phenyl-4-methylpyridine in 2 mL of carbontetrachloride was added 300 mg of sodium carbonate and 100 mg ofbromine. The reaction mixture was stirred and irradiated with a 500 Wlamp for 1 h, filtered and the solvent removed by evaporation underreduced pressure to yield 2-phenyl-4-bromomethylpyridine which was usedin the next step without further purification or characterization

To a solution of 2-phenyl-4-bromomethylpyridine in 5 mL of chloroformwas added 100 mg of 4-benzylpiperidine and 1 mL ofN,N-diisopropylethylamine. The reaction mixture was heated at refluxtemperature for 30 minutes, cooled to room temperature, washed with 5 mLof 1 N NaOH and the solvent removed by evaporation under reducedpressure. The product was purified by chromatography on silica gel using5% methanol in dichloromethane as eluent. Evaporation of the solventyielded a solid which was treated with ethereal-HCl to give 15 mg of2-phenyl-4-[(4-benzyl-piperidin-1-yl)methyl]-pyridine dihydrochloride(Compound 9), mp 222-225° C.

Example VI

The following compound was prepared essentially according to theprocedure described in Example V.

(a) 2-Phenyl-6-[(4benzyl-piperidin-1-yl)methyl]-pyridine (Compound 10),mp 81-83° C.

Example VII

A solution of 500 mg 5-bromo-2-phenyl-4-pyrimidinecarboxylic acid and 1mL N,N-diisopropylethylamine in 5 mL of ethanol was hydrogenated at 40psi of H₂ for 16 hr using 200 mg of 10% palladium-on-carbon as catalyst.The catalyst was filtered off and the ethanol removed by evaporationunder reduced pressure. The residue was dissolved in water, acidifiedwith 3 N hydrochloric acid and the precipitate was collected byfiltration. This material was air dried to yield 300 mg of2-phenyl-4-pyrimidinecarboxylic acid as a white solid which was used inthe next step without further purification or characterization. Asolution of 150 mg of 2-phenyl-4-pyrimidinecarboxylic acid in 1 mL ofthionyl chloride was heated at 70° C. for 1 hr, cooled to roomtemperature and the excess thionyl chloride removed by evaporation underreduced pressure to yield 145 mg of 2-phenyl-4-pyrimidinecarboxylic acidchloride which was used in the next step without further purification orcharacterization.

To a solution of 145 mg of 2-phenyl-4-pyrimidinecarboxylic acid chloridein 5 mL tetrahydrofuran was added excess lithium borohydride. Thereaction mixture was stirred at room temperature for 10 minutes thendiluted with 25 mL of ethyl acetate and filtered. The filtrate waswashed successively with 25 mL aliquots of 1 N sodium hydroxide andbrine. The solvent was removed by evaporation under reduced pressure toyield 100 mg of 2-phenyl-4-hydroxymethylpyrimidine as a white solid.

A solution of 55 mg 2-phenyl-4-hydroxymethylpyrimidine in 1 mL ofthionyl chloride was heated at reflux temperature for 1 hr and theexcess thionyl chloride removed by evaporation under reduced pressure toyield 50 mg of 2-phenyl-4-chloromethylpyrimidine as an oil which wasused in the next step without further purification or characterization.

To a solution of 50 mg of 2-phenyl-4-chloromethylpyrimidine in 5 mLchloroform was added 80 mg 4-benzylpiperidine and 1 mL ofN,N-diisopropylethylamine. The reaction mixture was heated at refluxtemperature for 4 hr, cooled to room temperature, washed with 5 mL 1 Nsodium hydroxide solution and the solvent removed by evaporation underreduced pressure to yield2-phenyl-4-[(4-benzyl-piperidin-1-yl)rnethyl]-pyrimidine. This materialwas purified by chromatography on silica gel using 5% methanol indichloromethane as eluent. Evaporation of the solvent yielded a solidwhich was treated with ethereal-HCl to give 15 mg of2-phenyl-4-[(4-benzyl-piperidin-1-yl)methyl]-pyrimidine dihydrochloride(Compound 11), mp 211-213° C.

Example VIII

The following compound was prepared essentially according to theprocedure described in Example VII.

(a) 2-phenyl-4-[(N-methyl-N-benzyl)aminomethyl]-pyrimidinedihydrochloride (Compound 12).

The disclosures in this application of all articles and references,including patents, are incorporated herein by reference.

The invention and the manner and process of making and using it are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the spirit or scope of the presentinvention as set forth in the claims. To particularly point out anddistinctly claim the subject matter regarded as invention, the followingclaims conclude the specification.

What is claimed is:
 1. A compound of the formula:

or the pharmaceutically acceptable salt thereof wherein: S and V are thesame or different and represent hydrogen, halogen, hydroxy, phenyl,straight or branched chain lower alkyl having 1-6 carbon atoms, orstraight or branched chain lower alkoxy having 1-6 carbon atoms; G and Kare the same or different and represent N or CR′ where R′ is hydrogen,halogen, straight or branched chain lower alkyl having 1-6 carbon atomsor straight or branched lower alkoxy having 1-6 carbon atoms; R ishydrogen or straight or branched chain lower alkyl having 1-6 carbonatoms; R₁, X, Y, Z and T are the same or different and representhydrogen, halogen, cyano, hydroxy, straight or branched chain loweralkyl having 1-6 carbon atoms, straight or branched lower alkoxy having1-6 carbon atoms or SO₂R₄ where R₄ is straight or branched chain loweralkyl having 1-6 carbon atoms or where R₄ is NH₂ or NHCH₃; R₂ and R₃ arethe same or different and represent hydrogen, straight or branched chainlower alkyl having 1-6 carbon atoms, aryl, arylalkyl; or NR₂R₃ togetherrepresent 2-(1,2,3,4-tetrahydroisoquinolinyl), either unsubstituted ormono or disubstituted with halogen, hydroxy, straight or branched chainlower alkyl having 1-6 carbon atoms, or straight or branched loweralkoxy having 1-6 carbon atoms; or NR₂R₃ represents:

where R₅ is phenyl, either unsubstituted or mono or disubstituted byeither halogen, hydroxy, straight or branched chain lower alkyl having1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6carbon atoms; or NR₂R₃ together represent

where W is N or CH; and R6 is phenyl, benzyl, pyridyl or pyrimidinyl,unsubstituted or mono or disubstituted with halogen, hydroxy, straightor branched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms; and n is 1, 2 or 3;provided that (a) R⁵ or R⁶ are not phenyl when K is CR′, G is N andNR₂R₃ represents

(b) R⁶ is not phenyl when G and K are N and NR₂R₃ represent

(c) R₂ and R₃ are not lower alkyl when R₁, X, Y, Z and T are hydrogen, Kand G are CH, S is hydrogen and V is hydroxy.
 2. A compound of theformula:

or the pharmaceutically acceptable salt thereof wherein: S and V are thesame or different and represent hydrogen, halogen, hydroxy, phenyl,straight or branched chain lower alkyl having 1-6 carbon atoms, orstraight or branched chain lower alkoxy having 1-6 carbon atoms; G and Kare the same or different and represent N or CR′ where R′ is hydrogen,halogen, straight or branched chain lower alkyl having 1-6 carbon atomsor straight or branched lower alkoxy having 1-6 carbon atoms; R ishydrogen or methyl; R₁, X, Y, Z and T are the same or different andrepresent hydrogen, halogen, cyano, hydroxy, straight or branched chainlower alkyl having 1-6 carbon atoms, or straight or branched loweralkoxy having 1-6 carbon atoms; R₂ and R₃ are the same or different andrepresent hydrogen, straight or branched chain lower alkyl having 1-6carbon atoms, aryl, arylalkyl; or NR₂R₃ together represent2-(1,2,3,4-tetrahydroisoquinolinyl), either unsubstituted or mono ordisubstituted with halogen, hydroxy, straight or branched chain loweralkyl having 1-6 carbon atoms, or straight or branched lower alkoxyhaving 1-6 carbon atoms; or NR₂R₃ represents:

where R₅ is phenyl, either unsubstituted or mono or disubstituted byeither halogen, hydroxy, straight or branched chain lower alkyl having1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6carbon atoms; or NR₂R₃ together represent

where W is N or CH; and R6 is phenyl, benzyl, pyridyl or pyrimidinyl,unsubstituted or mono or disubstituted with halogen, hydroxy, straightor branched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms; and n is 2;provided that (a) R⁵ or R⁶ are not phenyl when K is CR′, G is N andNR₂R₃ represents

(b) R⁶ is not phenyl when G and K are N and NR₂R₃ represent

(c) R₂ and R₃ are not lower alkyl when R₁, X, Y, Z and T are hydrogen, Kand G are CH, S is hydrogen and V is hydroxy.
 3. A compound of theformula:

or the pharmaceutically acceptable salt thereof wherein: S and V are thesame or different and represent hydrogen, halogen, hydroxy, phenyl,straight or branched chain lower alkyl having 1-6 carbon atoms, orstraight or branched chain lower alkoxy having 1-6 carbon atoms; R ishydrogen or straight or branched chain lower alkyl having 1-6 carbonatoms; R₁, X, Y, Z and T are the same or different and representhydrogen, halogen, cyano, hydroxy, straight or branched chain loweralkyl having 1-6 carbon atoms, straight or branched lower alkoxy having1-6 carbon atoms or SO₂R₄ where R₄ is straight or branched chain loweralkyl having 1-6 carbon atoms or where R₄ is NH₂ or NHCH₃; R₂ and R₃ arethe same or different and represent hydrogen, straight or branched chainlower alkyl having 1-6 carbon atoms, aryl, arylalkyl; or NR₂R₃ togetherrepresent 2-(1,2,3,4-tetrahydroisoquinolinyl), either unsubstituted ormono or disubstituted with halogen, hydroxy, straight or branched chainlower alkyl having 1-6 carbon atoms, or straight or branched loweralkoxy having 1-6 carbon atoms; or NR₂R₃ represents:

where R₅ is phenyl, either unsubstituted or mono or disubstituted byeither halogen, hydroxy, straight or branched chain lower alkyl having1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6carbon atoms; or NR₂R₃ together represent

where W is N or CH; and R₆ is phenyl, benzyl, pyridyl or pyrimidinyl,unsubstituted or mono or disubstituted with halogen, hydroxy, straightor branched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms; and n is 1, 2 or 3;provided that R⁶ is not phenyl when NR₂R₃ represents


4. A compound of the formula:

or the pharmaceutically acceptable salt thereof wherein: S and V are thesame or different and represent hydrogen, halogen, hydroxy, phenyl,straight or branched chain lower alkyl having 1-6 carbon atoms, orstraight or branched chain lower alkoxy having 1-6 carbon atoms; R′ ishydrogen, halogen, straight or branched chain lower alkyl having 1-6carbon atoms or straight or branched lower alkoxy having 1-6 carbonatoms; R is hydrogen or straight or branched chain lower alkyl having1-6 carbon atoms; R₁, X, Y, Z and T are the same or different andrepresent hydrogen, halogen, cyano, hydroxy, straight or branched chainlower alkyl having 1-6 carbon atoms, straight or branched lower alkoxyhaving 1-6 carbon atoms or SO₂R₄ where R₄ is straight or branched chainlower alkyl having 1-6 carbon atoms or where R₄ is NH₂ or NHCH₃; R₂ andR₃ are the same or different and represent hydrogen, straight orbranched chain lower alkyl having 1-6 carbon atoms, aryl, arylalkyl; orNR₂R₃ together represent 2-(1,2,3,4-tetrahydroisoquinolinyl), eitherunsubstituted or mono or disubstituted with halogen, hydroxy, straightor branched chain lower alkyl having 1-6 carbon atoms, or straight orbranched lower alkoxy having 1-6 carbon atoms; or NR₂R₃ represents:

where R₅ is phenyl, either unsubstituted or mono or disubstituted byeither halogen, hydroxy, straight or branched chain lower alkyl having1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6carbon atoms; or NR₂R₃ together represent

where W is N or CH; and R6 is phenyl, benzyl, pyridyl or pyrimidinyl,unsubstituted or mono or disubstituted with halogen, hydroxy, straightor branched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms; and n is 1, 2 or 3;provided that R⁵ or R⁶ are not phenyl when NR₂R₃ represents


5. A compound of the formula:

or the pharmaceutically acceptable salt thereof wherein: S and V are thesame or different and represent hydrogen, halogen, hydroxy, phenyl,straight or branched chain lower alkyl having 1-6 carbon atoms, orstraight or branched chain lower alkoxy having 1-6 carbon atoms; R′ ishydrogen, halogen, straight or branched chain lower alkyl having 1-6carbon atoms or straight or branched lower alkoxy having 1-6 carbonatoms; R is hydrogen or straight or branched chain lower alkyl having1-6 carbon atoms; R₁, X, Y, Z and T are the same or different andrepresent hydrogen, halogen, cyano, hydroxy, straight or branched chainlower alkyl having 1-6 carbon atoms, straight or branched lower alkoxyhaving 1-6 carbon atoms or SO₂R₄ where R₄ is straight or branched chainlower alkyl having 1-6 carbon atoms or where R₄ is NH₂ or NHCH₃; R₂ andR₃ are the same or different and represent hydrogen, straight orbranched chain lower alkyl having 1-6 carbon atoms, aryl, arylalkyl; orNR₂R₃ together represent 2-(1,2,3,4-tetrahydroisoquinolinyl), eitherunsubstituted or mono or disubstituted with halogen, hydroxy, straightor branched chain lower alkyl having 1-6 carbon atoms, or straight orbranched lower alkoxy having 1-6 carbon atoms; or NR₂R₃ represents:

where R₅ is phenyl, either unsubstituted or mono or disubstituted byeither halogen, hydroxy, straight or branched chain lower alkyl having1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6carbon atoms; or NR₂R₃ together represent

where W is N or CH; and R6 is phenyl, benzyl, pyridyl or pyrimidinyl,unsubstituted or mono or disubstituted with halogen, hydroxy, straightor branched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms; and n is 1, 2 or 3;provided that R⁵ or R⁶ are not phenyl when NR₂R₃ represents


6. A pharmaceutical composition comprising a compound according to claim1, and at least one pharmaceutically acceptable carrier or excipient. 7.A method of treating schizophrenia, depression or Parkinson's diseasecomprising administering to a patient in need of such treatment aneffective amount of a compound according to claim
 1. 8. A method oftreating cognitive disorders, memory impairment, or attention deficitdisorders comprising administering to a patient in need of suchtreatment an effective amount of a compound according to claim
 1. 9. Amethod of treating the extrapyramidyl side effects associated with theuse of neuroleptic agents comprising administering to a patient in needof such treatment an effective a mount of a compound according to claim1.